Ophthalmic examination and disease management with multiple illumination modalities

ABSTRACT

Imaging various regions of the eye is important for both clinical diagnostic and treatment purposes as well as for scientific research. Diagnosis of a number of clinical conditions relies on imaging of the various tissues of the eye. The subject technology describes a method and apparatus for imaging of the back and/or front of the eye using multiple illumination modalities, which permits the collection of one or more of reflectance, spectroscopic, fluorescence, and laser speckle contrast images.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/938,492, filed Jul. 24, 2020, which is a continuation of U.S. patentapplication Ser. No. 15/295,887, filed Oct. 17, 2016, now U.S. Pat. No.10,722,116, which is a continuation of U.S. patent application Ser. No.14/855,329, filed Sep. 15, 2015, now U.S. Pat. No. 9,492,083, which is acontinuation of International Application No. PCT/US2014/025014, filedMar. 12, 2014, which claims the benefit of U.S. Provisional ApplicationNo. 61/788,835, filed Mar. 15, 2013, the entirety of which isincorporated herein by reference.

GOVERNMENT LICENSE RIGHTS

This invention utilized government support under grant 1R43EY023018-01awarded by the National Eye Institute (of the National Institutes ofHealth). The government has certain rights in the invention.

FIELD

The subject technology relates to imaging regions of tissue. Inparticular, the subject technology relates to clinical diagnostic andtreatment modalities, ophthalmic examination, and disease management.

BACKGROUND

Imaging the internal regions of the eye is important for both clinicaldiagnostic and treatment purposes as well as for scientific research.Diagnosis of a number of clinical conditions (e.g., diabetic retinopathy(DR), hypertensive retinopathy (HR), age related macular degeneration(AMD), retinopathy of prematurity (ROP), retinal detachment, glaucoma,cataract, and various types of neovascularization pathologies in thechoroid (CNV), cornea and retina) relies on imaging appropriately theretina, choroid, the cornea, the sclera, or the eye lens, includingimaging specific aspects of each of these tissues (e.g., blood, bloodvessels, exudates, and other anatomical and physiological features). Anumber of these pathophysiologies are gradual—that is, these disordersdevelop over time-making a strong case for timely diagnosis andmanagement. For example, unmanaged diabetes and DR leads toproliferation of blood vessels in the retina, blood leakage into the eyeand eventually, loss of vision. Thus, not only does retinal imaging havea role in detecting the evidence of a pathophysiology, but also indiagnosing its severity. Early diagnosis through routine monitoring isimportant in disease management and so, eye screening is becoming anincreasingly important aspect in primary care.

In addition to these ophthalmic diseases, imaging of the blood vesselsof ophthalmic tissue can be used to detect non-ophthalmic diseases orconditions. These non-ophthalmic disease or conditions can beorgan-specific or systemic. For example, reports in literature have alsoindicated that early signs of brain disorders are also manifested in theretina. Thus, imaging the retina can be used for early diagnosis or riskassessment of conditions like stroke and other types of brain lesions.Similarly, systemic disease (e.g., heart disease or diabetes) can bediagnosed and monitored based on an evaluation of the retinal bloodvessels.

SUMMARY

The subject technology describes a method and apparatus for imaging ofthe back (i.e., the retina and/or the choroid) and/or front (i.e., thecornea and the sclera) of the eye using multiple illuminationmodalities. The use of multiple illumination modalities allows forimaging under, for example, coherent and incoherent illumination, thetiming of which can be controlled for the desired imaging technique.Coherent illumination means the degree of coherence of the emittedoptical beam is high (e.g., green, red, blue, or near infrared laser)and includes, among other things, diode lasers and vertical cavitysurface emitting lasers (VCSEL). Incoherent illumination means thedegree of coherence of the emitted optical beam is low (e.g., white orspectrally filtered light from a light emitting diode (LED) or a halogenlamp). Use of multiple illumination modalities permits the ophthalmicimaging device (called “OID” hereafter) to capture one or more ofreflectance images, absorption spectroscopic images, fluorescenceimages, and LSCI images with or without mydriatic agents.

The OID can be used both in the clinic and the laboratory to image thetissue of the eye of humans and animals to provide quantitativeanatomical and physiological information for assessment of tissuefunction and management of correlated diseases. Imaging of the tissue ofthe eye includes, for example, the imaging of anatomical features of theretina (e.g., the location, length, density, and type of blood vessels)and associated physiological parameters (e.g., blood flow rates,oxygenation, hematocrit, and changes in diameter, length, density,oxygenation, and hematocrit) that indicate retinal function. The OID canalso image blood, as in the case of hemorrhages and blood leakageresulting from blood vessel proliferation and damage. Thus, the OID canbe used to monitor the retinal anatomy and physiology for research anddiagnosis of a number of pathophysiologies (e.g., DR, HR, ROP, AMD, andretinal detachment). Similarly, the OID can be used to image thechoroid, the cornea, and the sclera to detect or evaluate diseases ofthese tissues (e.g., choroidal neovascularization). The OID can bedesigned either as different embodiments that are customized for theapplication but employ the principles disclosed herein, or as a singleembodiment that contains adjustable components providing for use in bothhumans and animals.

The OID can also be utilized to monitor efficacy of medicalinterventions in the eye during and after the procedure. Suchinterventions might be surgical (e.g., laser photocoagulation surgery orkeratoplasty) or chemotherapeutic (e.g., use of an anti-VEGF drug in theeye or investigation of eye drops). The OID can be used as a real-timeor near-real-time feedback mechanism during, for example, any surgicalprocedure where monitoring of vascular changes would be of relevance. Toillustrate this example, the OID can present the real-time LSCI imagesand blood flow parameters in front of the surgeon's eye using a displaymechanism built into a glasses-like device worn by the surgeon or usingsome physical or virtual screen viewable by the surgeon. The OID can beused as a therapy-planning tool (i.e., to guide medical interventions).For example, the OID can identify specific blood vessels that arecandidates for laser photocoagulation surgery in the eye and thisinformation can be presented to the surgeon for consideration. The OIDcan be used as a therapy control mechanism to automatically control, forexample, a computer-guided laser for blood vessel photocoagulation or totrigger the delivery or prescription of a specific medication. The OIDcan also be used for therapy-planning in a manner that allows thetherapy to avoid certain types of blood vessels.

The OID can be used to detect non-ophthalmic diseases or conditions.These diseases or conditions can be organ-specific or systemic. Forexample, the OID can be used for early diagnosis or risk assessment ofconditions like stroke and other types of brain lesions. Similarly,systemic disease (e.g., heart disease or diabetes) can be diagnosed andmonitored based on an evaluation of the anatomical and physiologicalinformation obtained with the OID (e.g., changes in retinal blood flowrates).

Finally, the OID can be incorporated into an electronic health records(EHR) system or a mobile disease management system as a feedbackmechanism to improve diagnosis or treatment of the specific diseasetarget. For example, the OID can automatically store the images obtainedinto the patient's EHR for subsequent viewing and analysis. In addition,the OID can automatically make notations in the EHR indicating a numberof important health information (e.g., the date of the most recent eyeexam, the risk level for a specific disease, and the specific values ofphysiological parameters indicative of the disease). The OID can alsoproduce a report of this information that can be incorporated into anEHR or other similar system and/or transmitted to an appropriatehealthcare provider, caregiver, or the patient.

An example of incorporating the OID into a mobile disease managementsystem is for early diagnosis and associated management of DR, acomplication of diabetes with symptoms in the eye. Diabetes and itsprogression could be tracked through routine monitoring of the eye usingthe OID and subsequent incorporation of the data into an EHR report.Such data can be stored in a time-stamped manner, and blood vesselinformation (e.g., vessel diameter and blood flow) could be comparedthrough graphs, image overlays, difference images, and othervisualization methods. Such data (and associated comparative analyses)could be made available to physicians and specialists for a moredetailed understanding of the history and current state of the disease,so that custom care can be provided.

According to some embodiments, an ophthalmic imaging device includes: A)an illumination module capable of generating a plurality of illuminationmodalities, wherein the illumination modalities include coherentillumination and incoherent illumination, and wherein the illuminationmodule can be configured to perform one or more of laser specklecontrast imaging, spectroscopic imaging, reflectance imaging, orfluorescence imaging; B) one or more imaging sensors configured tocollect light from the one or more regions of tissue of the eye; C) anoptical assembly including one or more optical elements configured todirect light from the illumination module to one or more regions oftissue of the eye, and further configured to direct light from the oneor more regions of tissue of the eye to the one or more imaging sensors;or a first optical assembly including one or more first optical elementsconfigured to direct light from the illumination module to one or moreregions of tissue of the eye and a second optical assembly including oneor more second optical elements configured to direct light from the oneor more regions of tissue of the eye to the one or more imaging sensors;wherein the one or more regions of the tissue of the eye include theretina, choroid, the cornea, the sclera, and the eye lens.

According to some embodiments, the one or more optical elements, the oneor more first optical elements, and/or the one or more second opticalelements can be an aperture that results in the production of a specklepattern on the one or more imaging sensors. The ophthalmic imagingdevice can further include one or more processors configured to controlthe arrangement of the one or more optical elements, to controldurations, duty cycles, and synchrony of the plurality of illuminationmodalities and the one or more imaging sensors, to control one or moreimage acquisition parameters, or to process data generated from the oneor more imaging sensors to perform one or more of laser speckle contrastimaging, spectroscopic imaging, reflectance imaging, and fluorescenceimaging. The one or more optical elements of the optical assembly can beconfigured to direct light to the one or more regions of tissue of theeye can include one or more spectrally selective filters configured torestrict the illumination from the one or more sources of incoherentillumination to one or more narrow bands of light, wherein the narrowbands of light include green light, blue light, red light, and nearinfrared light. The ophthalmic imaging device can further include one ormore neutral density filters configured to attenuate the illuminationpower of the one or more sources of coherent or incoherent illumination.The ophthalmic imaging device can further include one or more filtersconfigured to reject harmful wavelengths for a specific application. Thelight directed to the one or more regions of tissue of the eye caninclude one or more illumination beams generated from the illuminationmodule. The one or more illumination beams can be coaxial with theoptical axis of the imaging path. The one or more illumination beams canbe not coaxial with the optical axis of the imaging path. The lightdirected to the one or more regions of tissue of the eye from the one ormore illumination beams can occur synchronously or asynchronously.

According to some embodiments, the ophthalmic imaging device can furtherinclude one or more kinematic elements for engaging, indexing, or lineartranslation of the one or more optical elements, wherein the one or morekinematic elements includes stepper motors, rotors, gears, and guiderails. The ophthalmic imaging device can further include one or moremeans of user input, wherein the one or more means of user inputincludes one or more buttons, switches, touchscreens, physical orvirtual keyboards, or means to control a cursor. The ophthalmic imagingdevice can further include one or more means of data transmission touni-directionally or bi-directionally exchange information with one ormore storage devices, display devices, or processing devices, whereinthe one or more storage devices, display devices, or processing devicescan be standalone or associated with one or more remote computers orservers. The one or more processors can be further configured tocalculate laser speckle contrast values for pixels of the one or moreimaging sensors associated with the one or more regions of tissue of theeye, wherein the calculated laser speckle contrast values use propertiesof a pixel's neighborhood of pixels in spatial or temporal domains. Theone or more processors can be further configured to extract informationfrom data received, wherein the extracted information includes estimatesof blood velocity, estimates of blood flow, blood vessel diameters,spatial density of blood vessels, or classification of blood vessels asarterioles or venules. The one or more processors can be furtherconfigured to acquire an image stack and to register images of theacquired image stack to a reference image, wherein the reference imagecan be acquired independently or can be one of the images in theacquired image stack.

According to some embodiments, the ophthalmic imaging device can furtherinclude a gaze fixation mechanism to facilitate fixation of the eye'sgaze on a specified physical or virtual target using the contralateral,non-imaged eye. The gaze fixation mechanism can include an opticalassembly consisting of one or more optical elements, wherein the one ormore optical elements include lenses, filters, mirrors, collimators,beam splitters, fiber optics, light sensors, and apertures. The gazefixation mechanism can include one or more kinematic elements to adjustone or more optical elements. The gaze fixation mechanism projects animage of a physical or virtual object at a specified target locationwith respect to the imaged eye or the contralateral eye, wherein theprojected image can be determined prior to or at the time of imaging andthe projected image location varies during the course of imaging tofacilitate acquisition of images of different regions of the eye. Thegaze fixation mechanism can further include a display unit thatgenerates one or more virtual objects, the projected images of whichcoincide with the intended target for gaze fixation. The gaze fixationmechanism can further include a processing element to control operationof the gaze fixation mechanism and to perform one or more calculationsfor the operation of the gaze fixation mechanism, wherein the one ormore calculations include calculations pertaining to locationidentification of the intended target of gaze fixation and locationidentification of the virtual or physical object.

According to some embodiments, the ophthalmic imaging device can furtherinclude an immobilization mechanism for stabilization with respect tothe subject's eye, wherein the immobilization mechanism can include oneor more optical elements and one or more rigid components, wherein theone or more optical elements includes lenses, filters, mirrors,collimators, beam splitters, fiber optics, light sensors, and aperturesand the one or more rigid components includes a helmet or one or morenose bridges, sunglasses, goggles, rubber cups, helmets. The diseasemanagement system, can further include: A) one or more ophthalmicimaging devices configured to perform one or more of laser specklecontrast imaging, spectroscopic imaging, reflectance imaging, andfluorescence imaging of one or more regions of tissue of the eye,wherein the one or more regions of the tissue of the eye include theretina, choroid, the cornea, the sclera, and the eye lens; one or moresensors configured to collect at least one type of patient-specificdata. The disease management system can further include: one or moreprocessors configured to process the anatomical or physiologicalinformation from the one or more regions of tissue of the eye and the atleast one type of patient-specific data; and one or more interfacedevices configured to display the at least one type of patient-specificdata and to allow the user to input information to change thefunctionality of the one or more processors. The one or more ophthalmicimaging devices can be configured for one or more diagnostic,prognostic, or therapeutic purposes, wherein the one or more diagnostic,prognostic, or therapeutic purposes include ophthalmic andnon-ophthalmic diseases or conditions. The one or more sensors consistsof ophthalmic or non-ophthalmic sensors. The processor can be configuredto read and analyze the at least one type of patient-specific data fromone or more points in time, wherein the analysis includes comparing theat least one type of patient-specific data to one or more thresholds,comparing the at least one type of patient-specific data at differentpoints in time, calculating trends of the at least one type ofpatient-specific data, comparing trends of the at least one type ofpatient-specific data to one or more thresholds, extrapolating trends ofthe at least one type of patient-specific data to estimate the expectedfuture values of the at least one type of patient specific-data, andcomputing one or more threshold criteria based on population-basedstatistics associated with the one or more patient-specific data. Theone or more thresholds include one or more constant values or valuesthat depend on the attributes of the at least one type ofpatient-specific data, or values that depend on population-basedstatistics associated with the at least one type of patient-specificdata. The at least one type of patient-specific data includes one ormore electrocardiograms, blood pressure measurements, heart ratemeasurements, pulse oximetry measurements, blood glucose measurements,hemoglobin A1c measurements, ocular pressure measurements, respiratorymeasurements, plethysmograms, weight measurements, height measurements,age, body position, electroencephalograms, electrooculograms,electroretinograms, visual evoked responses, prior medical history, andinformation derivative to the at least one type of patient-specificdata. The processor can be configured to: trigger one or more types oftherapy through one or more manual, semi-automatic, or automatic means;and facilitate the communication of the at least one type ofpatient-specific data to one or more devices for storage, display, oranalysis.

According to some embodiments, a method of imaging a region of tissue ofthe eye, includes: configuring the ophthalmic imaging device for imageacquisition suitable to achieve the desired imaging modality, whereinthe configuring step includes maintaining a pre-configured state,adjusting one or more optical assemblies, illumination modalities, andimage acquisition parameters; initiating illumination generated by theophthalmic imaging device; initiating image acquisition based on theimage acquisition parameters; storing the acquired images; processingthe acquired images; and changing manually or through the configuredprocessing element of the ophthalmic imaging device, the source ofcoherent incoherent illumination and repeating one or more of theadjusting the optical assembly, setting values for image acquisitionparameters, initiating illumination, initiating image acquisition,storing, or processing steps.

According to some embodiments, the method can further includeimmobilizing an ophthalmic imaging device with respect to a subject'seye. The method can further include instructing the subject to fixatethe gaze of the eye on a physical or virtual object. The ophthalmicimaging device can be configured to acquire images using a plurality ofimaging modalities, wherein the plurality of imaging modalities includeslaser speckle contrast imaging, spectroscopic imaging, reflectanceimaging, and fluorescence imaging. The ophthalmic imaging device can behandheld and immobilized by resting or pressing against the subject'sface or eye. The ophthalmic imaging device can be used in conjunctionwith eyeglasses, goggles, a helmet, or other accessory to immobilize theophthalmic imaging device with respect to the subject's head or eye. Theophthalmic imaging device can be used in conjunction with a chin rest orother accessory to immobilize the subject's head or eye. The virtualobject can be generated by the ophthalmic imaging device and thelocation of the virtual object can be predetermined or determineddynamically by an operator. The optical assembly of the ophthalmicimaging device can contain one or more optical elements that can beadjusted manually by the operator, semi-automatically, or automaticallyby a processor. The image acquisition parameters can include exposuretime, gain, pixel sensitivity, number of images, frame rate, timingsequence, pixel resolution, pixel area, and image magnification. Theillumination generated by the ophthalmic imaging device can includelight from one or more coherent illumination beams and light from one ormore incoherent illumination beams. Storing the acquired images caninclude recording one or more images on a local or remote storagedevice, wherein the storage device includes any one or more of randomaccess memory, magnetic or solid state hard disk technology, flash disktechnology, or optical disk technology. The processing of acquiredimages can include registration of acquired images, processing for laserspeckle contrast imaging, feature extraction using a combination of oneor more of laser speckle contrast images, spectroscopic images,reflectance images, and fluorescence images, processing forspectroscopic imaging, and preparing images or processed images forcommunication, storage, or display.

According to some embodiments, a method of analyzing images obtainedusing an ophthalmic imaging device includes: selecting the one or moreimages and parameters to analyze; selecting the one or more processingalgorithms to perform; triggering the one or more processing algorithms;and presenting the output of the one or more processing algorithms.

According to some embodiments, the one or more images can be generatedfrom one or more of laser speckle contrast imaging, spectroscopicimaging, reflectance imaging, and fluorescence imaging. The one or moreparameters can be one or more of anatomical and physiological parametersextracted from one or more images generated from one or more of laserspeckle contrast imaging, spectroscopic imaging, reflectance imaging,and fluorescence imaging. The one or more parameters can be extractedfrom one or more sensors and includes electrocardiograms, blood pressuremeasurements, heart rate measurements, pulse oximetry measurements,blood glucose measurements, hemoglobin A1c measurements, ocular pressuremeasurements, respiratory measurements, plethysmograms, weightmeasurements, height measurements, age, body position,electroencephalograms, electrooculograms, electroretinograms, visualevoked responses, prior medical history, and information derivative tothe one or more parameters. The output can include one or more visualrenditions of the one or more images, the one or more parameters,thresholds, trends, and information derivative to the one or moreparameters. The method can further include one or more interface devicesconfigured to allow an operator to manipulate one or more of theselecting of the one or more images and parameters to analyze, theselecting of the one or more processing algorithms to perform, thetriggering of the one or more processing algorithms, and the presentingof the output of the one or more processing algorithms. The method canfurther include triggering therapy manually, semi-automatically, orautomatically based on the one or more analyzed images or parameters.The therapy includes one or more of a recommendation to the user tochange a specific drug medication or to perform some other treatmentprocedure, a recommendation that allows the user to trigger an automatictreatment or procedure, or an automated signal that controls a treatmentmechanism.

According to some embodiments, a method of managing a patient's diseaseincludes: acquiring one or more images of one or more regions of thetissue of the eye using an ophthalmic imaging device; acquiring at leastone type of patient-specific data from one or more sensors; processingthe one or more images, one or more parameters, and at least one type ofpatient-specific data; and presenting the processed information forreview by a caregiver.

According to some embodiments, the ophthalmic imaging device can beconfigured to generate the one or more images from one or more of laserspeckle contrast imaging, spectroscopic imaging, reflectance imaging,and fluorescence imaging. The method can further include triggeringtherapy manually, semi-automatically, or automatically based on the oneor more processed information.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic of the OID showing the functional components andoptical paths used for acquisition of reflectance, spectroscopic,fluorescence, and laser speckle contrast images of the retinal tissue ofthe eye.

FIG. 1B is a schematic of the electrical components of the OID.

FIGS. 2A and 2B illustrate various embodiments of the illuminationmodule of the OID.

FIGS. 3A and 3B are illustrations of various embodiments of theillumination module comprising more than one light source.

FIG. 4 illustrates various embodiments of the beam deflector.

FIGS. 5A, 5B, and 5C illustrate various embodiments of the OpticalAssembly A and its relation to the field of view of the target tissueilluminated by the OID.

FIG. 6 is a schematic of the OID and an embodiment of a mechanism usedto induce a subject to fixate the gaze to facilitate image acquisition.

FIG. 7 is a schematic of an embodiment for immobilizing the OID withrespect to the subject's eye.

FIGS. 8A and 8B illustrate various embodiments for the incorporation ofthe OID into a standalone system that can be operated by non-expertsusing a simple interface.

FIG. 9 is a flowchart illustrating a method for using the OID to acquireimages of the target tissue in accordance with the embodiments of thesubject technology.

FIG. 10 is a flowchart illustrating a method for acquiring, processing,storing, and displaying the images obtained using the OID.

FIG. 11 is a flowchart illustrating a method for analyzing imagesobtained using the OID for disease progression assessment andmanagement.

FIGS. 12A and 12B are schematics for various embodiments of a diseasemonitoring and management system incorporating the OID.

FIGS. 13A, 13B, and 13C illustrate various embodiments for presentingand assessing parameters generated using the OID in accordance with thevarious embodiments of the subject technology.

DETAILED DESCRIPTION

A number of imaging modalities have been developed that may be ofrelevance for ophthalmic imaging. These include:

-   -   (a) Laser speckle contrast imaging. When images are acquired        under coherent (i.e., laser) illumination through an        appropriately sized aperture, speckle patterns are formed. The        blurring of speckle patterns due to motion can be mathematically        estimated using a metric called speckle contrast, defined as the        ratio of standard deviation of pixel intensities to the mean        value of pixel intensities within a specified neighborhood of        every pixel under consideration in the stack of images. The said        neighborhood may lie in the spatio-temporal domain, as described        in (1).    -   (b) Spectroscopic imaging. When images acquired under different        illumination wavelengths are compared, it is possible to        highlight features based on differential absorption,        transmission, and reflection of light by different tissue/cell        types. For example, differential analysis under near-infrared        and green light can distinguish between oxygenated and        deoxygenated blood.    -   (c) Reflectance imaging. This imaging mode is equivalent to        photographing the eye under illumination that is similar to        ambient light (e.g., light from a flashlight, light from a        halogen lamp, etc.). These images also contain information        analogous to spectroscopic images, since white light        intrinsically contains multiple wavelengths of light. Oxygenated        blood (in arteries under normal conditions) appears faint on a        grayscale image obtained under white light illumination, while        deoxygenated blood (in veins under normal conditions) appear        darker.    -   (d) Fluorescence imaging. If a fluorescent dye is injected in        the blood vessels, then high contrast images of blood vessels        could be obtained using appropriate illumination wavelengths and        optical filters.

Imaging the retina and/or the choroid poses a number of technical andpractical challenges:

-   -   (a) Given the constraints placed by motion artifact on the        camera exposure time in non-stabilized photography, ambient        light does not provide adequate illumination for photographing        the retina. Very little amount of light is captured by the        camera sensor within the small exposure time limiting its        ability to achieve high contrast between retinal features. Thus,        additional illumination from an external light source is        essential.    -   (b) The geometry of the eye-specifically, the location of the        retina, the pupil (and iris), the cornea and lens-does not        provide enough leeway for the illumination and imaging paths to        be along significantly different directions. This problem has        been partially solved in the past using an optical assembly        known as a fundus camera. However, the fundus camera cannot        perform laser speckle contrast imaging, a method of imaging        blood vessels and blood flow.    -   (c) Incidence of the illuminating light, especially coherent        light (i.e., laser) on the retina may be harmful, thus placing a        stringent constraint on the amount of energy that can be        delivered to the retina to provide illumination for imaging        purpose. Conventional retinal imagers that use lasers (e.g.,        scanning laser ophthalmoscopes) ensure through scanning that the        laser illuminates a small region of interest (ROI) for a very        short period of time, thus restricting the energy delivered to        the retina despite using a beam of high power and intensity.        Laser speckle contrast imaging (LSCI) requires simultaneous        illumination of the entire field of view (FOV) as opposed to        spot illumination and scanning—for longer periods of time in        comparison to prior laser-based retinal imaging techniques. The        overall illumination time could be as long as 10 seconds. Thus,        a low-power laser whose power may be duly attenuated further        must be used; and the activation and deactivation of the laser        module must be controlled using a mechanical shutter or an        electronic switch.    -   (d) Current retinal imagers place a significant socio-economic        burden on its use. The high cost of individual components that        make up the retinal imager, makes the overall system expensive.        Combining the cost of the device with the additional cost of the        eye-care specialists required to perform the procedure drives up        the cost of eye exams and overall healthcare expenditures.        Further, most retinal imagers require chemically-induced pupil        dilation to capture a large FOV, which makes their use        complicated and inconvenient.

As described in more detail below, the OID is composed of a plurality ofoptical elements, illumination modules, cameras, photosensors, powersources, processor elements, storage elements, and communicationelements. The specifications and parameters of the imager may change toaccommodate differences in the subjects' eyes. For example, rat eyes(used in research) are much smaller in size that human eyes. The rat eyecurvature is also different than the curvature of the human eye. Also,the apparatus may be embodied differently for different tissue beingimaged. For example, imaging the choroid may require illumination at ahigher wavelength than when imaging the retina. Likewise, imaging thecornea may require a different lens assembly than when imaging theretina. The apparatus may also be embodied with adjustable elements thatcan be moved and/or tuned for specific applications.

Some embodiments incorporate the OID into an external system for diseasemanagement and treatment. In some embodiments, the OID communicates withthe external system through a wireless connection. In other embodiments,the OID communicates with the external system through a wiredconnection. In some embodiments, the OID is incorporated into theexternal system to present data for review and tracking by a healthcareprovider. In other embodiments, the OID is incorporated into theexternal system to recommend specific treatment options. In otherembodiments, the OID is incorporated into the external system toautomatically control therapy.

FIG. 1A shows an exemplary OID 100 with the functional components andoptical paths used for acquisition of images of the target tissue 175 ofthe back of the human eye 170. Light produced by the illumination module110 is deflected off the beam deflector 117 and manipulated by OpticalAssembly A 120 to illuminate the target tissue 175 (e.g., the patient'sretina). This path of light from the illumination module 110 to thetarget tissue 175 is referred to as the illumination path 116, with thelight itself being referred to as the illumination beam. The opticalaxis of the portion of the illumination path 116 from the illuminationmodule 110 to the beam deflector 117 is called the illumination axis115. Light reflected from and/or scattered by the target tissue 175 maybe manipulated by a combination of Optical Assembly A 120 and OpticalAssembly B 130 en route to the image acquisition module 140. This pathof light from the target tissue 175 to the image acquisition module 140is referred to as the imaging path 135 and the optical axis of this pathis referred to as the imaging axis 180. The image acquisition module 140comprises an imaging sensor (e.g., a camera) 145 with the necessarycontrol, processing, and storage elements (e.g., a computer) to acquire,process, and store images of the target tissue 175. The OID 100 cancontain a separate processor unit 150 for controlling all or portions ofthe functional components. Furthermore, the OID 100 contains a powermodule 154 to provide electrical supply to all or portions of thefunctional components.

The illumination module 110 can be composed of a plurality of lightsources in a plurality of arrangements. The illumination module 110allows sequential imaging under at least one coherent and at least oneincoherent illumination beam. The at least one coherent illuminationbeam can be generated from green, red, blue, or near infrared laser. Theat least one incoherent illumination beam can be generated from white orspectrally filtered light from, for example, an LED or a halogen lamp.The illumination module 110 may be oriented such that the illuminationaxis 115 is oriented at an angle θ 121 with respect to the imaging axis180.

The beam deflector 117 can be a mirror or any other reflectiveobject/material oriented at a predetermined angle φ 118 with respect tothe illumination axis 115 such that the illumination path 116 can bedirected towards the target tissue 175. In other embodiments, angle φ118 can be determined with respect to the imaging axis 180 instead ofthe illumination axis 115. In other embodiments, angle φ 118 may bedetermined based on mechanical elements or casing of the OID 100. Thebeam deflector 117 is also chosen and located such that it facilitatesor does not interfere with the travel of light from the target tissue175 to the image acquisition sensor 145 along the imaging path 135. Insome embodiments, the beam deflector 117 may be located on one side ofthe imaging axis 180. In some embodiments, the beam deflector 117 maycontain a hole for the light reflected from the target tissue 175 toproceed towards the image acquisition module 140. In some embodiments,the beam deflector 117 may be a beam splitter which reflects a portionof the illumination light towards the target tissue 175 while lettingthe remaining light to pass through. Such a beam splitter will alsoallow a portion of the light reflected from the target tissue 175 topass through along the imaging path towards the image acquisition module140. The ratio of transmitted light and reflected light is a property ofthe beam splitter and may be anything from 0 to 1. Angle θ 121 may varyfrom 0° to 180° and angle φ 118 may vary commensurately so as to deflectthe illumination path 116 as much along the imaging axis 180 aspossible.

Optical Assembly A 120 can be composed of one or more lenses that focusthe illuminating light such that the target tissue 175 is illuminatedover a large FOV. In some embodiments, the Optical Assembly A 120 can bepositioned between the beam deflector 117 and the illumination module110 such that no lens is necessary in the illumination path 116 from thebeam deflector 117 to the target tissue 175. Optical Assembly A 120 canbe oriented such that it influences the imaging path 135 and theillumination path 116. In some embodiments, Optical Assembly A 120 isoriented such that it influences only the illumination path 116, thatis, light from the illumination module 110 may encounter OpticalAssembly A 120 before it encounters the beam deflector 117.

Optical Assembly B 130 comprises a minimum of one lens that focuses thelight from the target tissue 175 on the imaging sensor 145 and oneaperture that is central to the formation of speckle patterns on theimaging sensor 145. These elements could appear in any order in theimaging path 116. In one embodiment, the order is determined to achievethe dual function of image formation and speckle formation on theimaging sensor. In another embodiment, the lens and aperture arrangementcan be replaced by a system of lenses and apertures. Optical Assembly B130 typically comprises a mechanism to adjust the lens position forappropriate focusing. The mechanism of adjustment can involve movementof one or more lenses and/or apertures along the imaging axis 180. Suchmovement may be manual, semi-automatic (i.e., motorized butuser-triggered and/or controlled) or automatic (i.e., motorized and/orelectronically controlled without user intervention). In someembodiments, the adjustment mechanism moves at least 1 cm, though thisdistance depends on the focal lengths of the lenses used. In someembodiments, alternative adjustment approaches may be employed,including use of a movable camera with a fixed lens system.

The Optical Assembly B 130 is oriented such that it influences only theimaging path 135 and not the illumination path 116. Thus, the objectivesof Optical Assembly B 130 are: (a) to form an appropriately sized (i.e.,magnified) and appropriately focused image of the target tissue 175 onthe imaging sensor 145 or for direct viewing, (b) to achieve apre-calculated speckle size (i.e., Airy disc diameter) that lies between5 and 20 micrometers at the imaging sensor 145, and (c) to spectrallyfilter light en route from the target tissue 175 to the imageacquisition module 140 in case fluorescence or spectroscopic imaging isbeing performed. Accordingly, in one embodiment, Optical Assembly B 130comprises lens and aperture arrangements that can achieve a 1:1magnification and a speckle size of approximately 10-12 micrometers. Anymagnification between 0.5 and 2.0 and speckle sizes between 5 and 20micrometers may be acceptable depending on the embodiment and itspreferred application.

In some embodiments, particularly those that incorporate fluorescenceimaging, Optical Assembly B 130 may include one or more filters. Thesaid filter set can block the illuminating light while letting thefluorescently emitted light to pass through. For example, if fluoresceinangiography is being performed, the OID 100 can employ a filter thatselectively transmits green (approximately 520 to 540 nm) wavelengths,while blocking all others.

Optical Assembly A 120 and Optical Assembly B 130 are consideredseparately only for the sake of explanation. In some embodiments, theoptical elements of Optical Assembly A 120 and Optical Assembly B 130may seamlessly substitute the elements of the other. In someembodiments, a lens in Optical Assembly A 120 can be designed (e.g.,fusing different lenses together) such that an image can be formedwithout the need for any subsequent focusing en route to the imagingsensor 145 and, therefore, Optical Assembly B does not require adifferent lens. Such a lens—ostensibly a single optical element—becomesa functional part of both Optical Assembly A 120 and Optical Assembly B130.

The image acquisition module 140 comprises at least one imaging sensor145 that can capture the light coming from the target tissue 175 andstore the data in digital form as one or more images. Thus, the at leastone imaging sensor 145 includes charge coupled device (CCD) cameras,metal oxide semiconductor (MOS), complementary MOS (CMOS) cameras,photodiodes, phototransistors, and/or photo tubes. Digitization of thelight sensor data can be done immediately after sensing, as in mostcameras, or an analog-to-digital convertor (ADC) may be used subsequentto an analog camera. The imaging sensor 145 may or may not have anembedded processor as part of the OID 100. In one embodiment, a fieldprogrammable gate array (FPGA) or an equivalent programmable unit mayprocess the images acquired and store the image or relay the resultingimage for further consideration. In another embodiment, the imagingsensor 145 may store the acquired image(s) on to a memory device (e.g.,a flash disk), which then may be used to transfer the data for furtherprocessing. In a third embodiment, the imaging sensor 145 may beconnected to a processor and storage unit through a communicationchannel (e.g., the universal serial bus (USB)) and relay the acquiredimages in real-time or near real-time to a nearby processing unit (e.g.,computer or embedded processor). Other communication channels that canachieve a similar function are the IEEE 1394 (fire wire) ports,serial/parallel port, IDE, and/or the serial/parallel ATA. Imagetransfer may also be performed using wireless modules that utilize oneor more of Wi-Fi, 2G, 3G, 4GLTE, Bluetooth, and infrared channels.Transmission of the data may utilize any of the acceptable formats(e.g., DICOM, HL7, or other similar standards) for image transmissionand compliant with health data and internet security standards. Data maybe processed exclusively for the intention of transmission (e.g.,encryption for security, compression for transmission speed, etc.) andcommensurately processed again (e.g., decryption, decompression, etc.)at the receiving system for further use, processing or display.

The size and type of the storage element 152 is dependent on theembodiment of the OID 100. For example, the storage element can be large(e.g., 16 to 256 GB) to accommodate local storage for subsequent 1)viewing on a user interface module 153 (e.g., liquid crystal display)built into the OID 100, 2) image analysis, and 3) transmission to anexternal computing platform (e.g., for remote storage, analysis, ordisplay). Alternatively, the storage element can be small (e.g., 1 to 16GB) to accommodate temporary local storage for transmission to anexternal computing platform (e.g., for remote storage, analysis, ordisplay). The storage element could utilize any of random access memory(RAM) technology, magnetic or solid state hard disk technology, flashdisk technology, or optical disk technology.

The OID 100 contains a power module 154 that can be a combination of oneor more of direct current (DC) sources and alternating current (AC)sources converted through an AC to DC adaptor. For example, oneembodiment incorporates use of one or more non-rechargeable batteriesthat power all electronics within the OID 100. Another embodiment mayincorporate one or more rechargeable batteries in conjunction with an ACto DC adaptor. Each electronic element of the OID 100 may draw powerfrom sources independent of other electronic elements. For example, theimage acquisition module 140 may draw power from a USB, while theillumination module(s) 110 may use dedicated rechargeable ornon-rechargeable batteries.

The beam deflector 117 may lie in the imaging path 135 instead of theillumination path 116. In such an embodiment, the path of light from theillumination module 110 to the target tissue 175 may lie along a singlestraight line, but the path of light from the target tissue 175 to theimaging acquisition module 140 may involve one or more deflections byappropriately positioned beam deflectors 117. Whether in theillumination path 116 or the imaging path 135, the purpose of the beamdeflector 117 is to alter the direction of light leading up to it andorient the light in the desired direction. This function can also beachieved using one or more fiber optic cables and/or optical waveguides.Fiber optic cables are often flexible along their length and thus, relaxspace and position constraints on the illumination module 110.

FIG. 1B shows a schematic of the electrical components of an exemplaryOID 100. A switch 161 allows the user to activate or deactivate thefunctionality of the OID 100 while one or more batteries 162 power theelectrical components. In some embodiment, the one or more batteries 162can power some or all of the electrical components of the OID 100. Insome embodiments, the one or more batteries 162 may be incorporatedwithin the OID 100, while in other embodiments, one or more of thebatteries 162 can be external. A telemetry transceiver 151 allows datato be transmitted to and from the OID 100. In some embodiments, thetelemetry transceiver 151 may be replaced by another communicationmechanism. A processor unit 150 processes signals from the variouselectrical components, including the illumination module 110, OpticalAssembly A 120 and Optical Assembly B 130, and the image acquisitionmodule 140. The illumination module comprises a light source circuitryunit 111 and a stepper motor unit 112 to manipulate the light source113. The Optical Assembly A 120 comprises sensor circuitry 122 and astepper motor unit 123. The Optical Assembly B 130 comprises sensorcircuitry 131 and a stepper motor unit 132. The image acquisition module140 comprises sensor circuitry 141, a processor unit 142, and a datastorage unit 143.

The control of the various modules of the OID 100 can be achieved usingany processor unit 150. Examples of control activity include: invokingthe appropriate illumination module 110 for an appropriate amount oftime, motion of the components of the Optical Assembly A 120 and OpticalAssembly B 130 for focusing on appropriate ROI of the target tissue 175,control of the gaze fixation apparatus (described below), recording andbasic processing of images under appropriate illumination, invoking theappropriate modality for storage and/or transmission of the images,power management, data management and storage, and invoking advancedanalytics on the images. One embodiment will have the processor unit 150physically located on the OID 100 and could be an FPGA, amicroprocessor, or a microcontroller. Another embodiment has theprocessor unit 150 located remotely and communication to and from theOID 100 will be established via a telemetry transceiver 151, USB, or anyother standard or proprietary channels.

FIGS. 2A and 2B show exemplary embodiments of the illumination module110. The illumination module 110 contains one or more illuminationsources 205, along with optical elements for manipulating the beam(e.g., collimation or focusing) and appropriate filters. In oneembodiment, one or more filters 210, 220, and 230 are used to select forband of wavelengths (i.e., spectral filters). In another embodiment, oneor more filters 215 attenuates the intensity and power of illumination(i.e., neutral density filters) while one or more filters 225, 226, 227,228, and 229 are used to select for a band of wavelengths. In oneembodiment, selecting for a band of wavelengths is implemented to rejectharmful wavelengths for a specific application (e.g., retinal imaging).For example, infrared wavelengths may be selectively blocked using asuitable filter. These filters may use any mechanism (e.g., absorption,reflection, etc.) to achieve the desired function. Filters can bemounted anywhere in the illumination path 116, though it is common toinclude them as close to the light source 205 as possible. In someembodiments, filters are mounted on one or more filter wheels 240 thatrotate to invoke one or more of the filters or filter combinations. Insome embodiments, filters are mounted on one or more filter slides thatmove linearly to invoke one or more of the filters or filtercombinations. Movement of such filter wheels or slides may be manual,semi-automatic (i.e., motorized but user-triggered and/or controlled) orautomatic (i.e., motorized and/or electronically controlled without userintervention).

The illumination sources 205 typically include the following types ofillumination and wavelengths:

-   -   (a) Red laser (approximate range: 625-655 nm)    -   (b) Green laser (approximate range: 520-545 nm)    -   (c) Blue laser (approximate range: 460-495 nm)    -   (d) Near infrared (NIR) laser (approximate range: 700-900 nm)    -   (e) White light illumination from LEDs, halogen lamps, etc.    -   (f) Red, green, blue or NIR light from appropriate LEDs or        achieved by spectrally filtering white light (wavelength ranges,        as indicated for lasers, above).

In an embodiment designed for LSCI, the illumination source 205 in theOID 100 comprises one or more lasers or an equivalent coherentillumination source. In another embodiment designed for acquiringreflectance and/or fluorescence images or for viewing for interpretationor focusing (e.g., in preparation for image acquisition), theillumination source 205 is one or more incoherent illumination sources.

Not all applications will require the use of all illumination sources orillumination modalities. For example, green illumination mode can beachieved by switching on a white light source with a green filter in theoptical path and an appropriate neutral density filter to attenuate theintensity to the desired value. Such a green illumination mode may beprovided in the OID 100 to provide the user/operator/interpreter withmore information about the FOV. The OID 100 may not necessarily use thismode during every use/operation. Likewise, elucidation of microvascularflow in the retina may require only a 635 nm (red) laser illumination tobe invoked while segmentation of vessels into arteries and veins mayrequire both the red laser as well as white illumination modes to beinvoked sequentially.

The OID 100 may be used to perform fluorescence imaging, in which casethe illumination source 205 and associated spectral filter will dependon the dye being used. For fluorescein angiography, the illuminationwill be in the blue region of the electromagnetic spectrum, that is, itswavelength will lie in the range between 460 nm and 495 nm. Forindocyanine green (ICG) angiography, the illumination may lie between700 nm and 820 nm. Specific illumination patterns can be created byswitching “on” and “off” the appropriate light source, together withpre-assembled, manual, or motorized control of filter sets.

The illumination module 110 may also contain one or more apertures(e.g., pinhole aperture, slit aperture, or circular apertures) ofvarious sizes for finer control of illumination. Such an aperture may befixed or adjustable, much like the filters described above. For example,one embodiment can incorporate an aperture wheel, analogous to thefilter wheel 240, which can be rotated to invoke the apertureappropriate for the desired illumination mode. Another embodiment canincorporate adjacent apertures which can be slid into and out ofposition for a similar purpose.

FIGS. 3A and 3B illustrate embodiments of the illumination module 110comprising at least one coherent light source 306 (e.g., a laser) andone incoherent light source 306 (e.g., a halogen lamp). More sources maybe added depending on the application. For example, instead of using asingle white light LED in conjunction with a red filter and a greenfilter to obtain red and green light, two dedicated light sources (e.g.,a green LED and a red LED) may be used. Alternatively, two white lightLEDs with a dedicated red filter and a dedicated green filter,respectively, may be used.

FIG. 3A shows selective activation and deactivation of the light sourcesthrough mechanical indexing. A mechanical means may be included as partof the OID 100 that can orient each light source (along with associatedfilters) such that the emitted beam is along the illumination axis 115.The source may be moved with respect to the illumination axis 115, orthe source may be kept fixed along the illumination axis 115 and filtersand/or shutters moved with respect to the source to selectively appearin the illumination path 116. Indexing may be done manually or usinglinear/rotary motor(s) 320 with or without gear assemblies 325. In oneembodiment, a stepper motor is used for tight and programmed control ofthe angle of rotation 335 or the distance of linear translation 330.Rotary motion can be used to engage the desired illumination source 305or 306 using a stepper motor 320 located along 321 or orthogonal to 326the indexing axis 310.

FIG. 3B shows selective activation and deactivation of the light sourcesthrough electronic switching. The illumination sources 305 and 306 maybe immobilized in the illumination module 110 and their selectiveactivation and deactivation may be performed by switching them “on” or“off” electronically through an illumination control module 340. Such acircuit may directly control the power fed to the illumination sources305 and 306 and/or the timing of illumination (e.g., start time,duration, and duty cycle). A beam splitter 350 or equivalent arrangementallows the light from the illumination sources 305 and 306 to beoriented along the illumination axis 115.

The illumination module 110 can employ a combination of mechanical andelectronic switching for enhanced control of the illumination sources305 and 306. For example, the white light source may be switched “on”and “off” electronically, but red and green filters may be mechanicallyindexed in the path of the white light to achieve the red lightillumination mode and the green light illumination mode respectively.The trigger for mechanical indexing or electronic switching or both maybe manual, automatic, or semi-automatic. For example, in a manualembodiment, the user can rotate a spring loaded indexing mechanism toselectively engage the illumination source 305 and orient it along theillumination axis 115, while simultaneously disengaging the otherillumination source 306. In an automatic embodiment, a pre-set timingsequence or other control mechanism may be used to selectively engageeach source for a fixed amount of time. Such a timing sequence may beprovided to the switch circuit through a processor or to a motorizedindexing mechanism. In a semi-automatic embodiment, the user can move adesired filter into position, then press a push button that causes oneillumination source 305 switch “off” after a period of time and anotherillumination source 306 to switch “on”.

FIG. 4 illustrates various embodiments of the beam deflector 117. Thebeam deflector 117 may be a plane mirror 417A, concave mirror 417B, orconvex mirror 417C as long as the purpose served by the beam deflector117 in conjunction with the illumination module 110 and Optical AssemblyA 120 is to produce a beam of light convergent at or just in front ofthe target tissue (for imaging of the front of the eye) or the pupil(for imaging the back of the eye). In one embodiment for imaging of theretina, the beam deflector 117, illumination module 110, and OpticalAssembly A 120 are configured to produce a beam of light convergent ator just in front of the pupil of the subjects eye 170. The beamdeflector 117 function could also be achieved using a prism 417D orcombination of prisms 417E and 417F made of an optically transparentelement, such as a glass or plastic that uses total internal reflectionto deflect the beam of light in the desired direction. Likewise, it isalso possible to combine or fuse the beam deflector 117 with elements ofOptical Assembly A 120 and/or Optical Assembly B 130. The beam deflector117 may also be a beam splitter 417G that reflects a portion of thelight incident on it, while transmits the remainder.

FIGS. 5A, 5B, and 5C illustrate various embodiments of the OpticalAssembly A 120 and its relation to the FOV of the target tissue 175illuminated by the OID 100. In some embodiments, the Optical Assembly A120 influences both the illumination path 116 as well as the imagingpath 135 and may contain one or more optical elements (e.g., lenses,filters, mirrors, collimators, beam splitters, fiber optics, and lightsensors) to direct light along the illumination path 116 to the targettissue 175 and light along the imaging path 135 to the image acquisitionmodule 140.

FIG. 5A shows an exemplary Optical Assembly A 120 of an OID 100 thatcontains two lenses 510 and 511. In some embodiments, the OpticalAssembly A 120 contains one lens, while in other embodiments the OpticalAssembly A 120 contains more than one lens. All or some of the lensescan be fixed or adjustable. In this embodiment, the location of one lens510 is fixed by a mechanical mount 520 while the second lens 511 isattached to an adjustable mount 521, which can be controlled manually,semi-automatically, or automatically. This exemplary embodiment can alsodescribe the embodiment of Optical Assembly B 130.

FIGS. 5B and 5C show the influence of pupil dilation on the FOV (i.e.,the area of the target tissue 175 that is imaged). Illuminating the backof the subject's eye 170 through an undilated or narrow pupil 530results in a small FOV 535. Conversely, illuminating the back of thesubject's eye 170 through a dilated or wide pupil 540 results in a largeFOV 545.

In an embodiment that uses LSCI to image the retina, the OpticalAssembly A 120 can be designed such that: (a) the FOV is as large aspossible, (b) the light intensity at the retina never exceeds a safetythreshold, (c) the desired imaging technique can be achieved through thesubject's dilated or undilated pupil, and (d) the subject's pupil doesnot become critical in determining the speckle size. To meet theobjectives (a), (b) and (c), the effective focal length of OpticalAssembly A 120 should be less than 25 mm. In this embodiment, theillumination beam will converge at the pupil or just in front of thepupil, so that light entering the eye is a divergent beam andilluminates a large FOV 525. The distance 552 between the retina and thepupil is approximately 20 mm in human adults, and a beam diverging overthis distance will decrease the risk of over exposure at the retina(than a beam that is convergent or parallel over the same distance). Theundilated (and also unconstricted) pupil 530 is approximately 3-4 mm indiameter in human subjects. Thus, a circular region with diameter of ˜1cm on the retina can be illuminated if Optical Assembly A 120 convergesthe illumination path 116 such that the half-angle ψ 560 that the beamenvelope makes with the imaging axis 180 is greater than 11 degrees.Much of the illuminating light will enter the pupil if the point wherethe beam diameter is the smallest lies on the focal plane 551 5-7 mmfrom the pupil.

In another embodiment, illumination of the entire FOV 525 may beachieved through illumination of multiple smaller overlapping areas onthe target tissue 175. The advantage of such an arrangement is toprevent the illumination beam from being centered at the imaging axis180 (called off-center illumination) so that back reflection fromelements of Optical Assembly A 120 or non-relevant portions of thetarget tissue 175 (e.g., reflection from the cornea when the targettissue is the retina) is reduced, increasing contrast at the imagingsensor 145. In one embodiment, annular illumination at the pupil 530 isemployed to achieve off-center illumination. In another embodiment, theillumination beam is split into multiple illumination beams, each ofwhich is not coaxial with the imaging axis, and Optical Assembly A 120is utilized to focus each of these multiple illumination beams toconverge at or in front of the pupil 530 (e.g., on the focal plane 551)but not on the imaging axis 180 as described above. In this embodiment,the resulting illumination of the entire FOV 525 will be produced by thesuperposition of the individual and overlapping FOVs of each of thesemultiple illumination beams.

The above calculations for increasing the FOV without pupil dilation areexplained on the basis of the geometry of an average healthy humanadult, but the same can be achieved for varying eye sizes and eyeconditions and for each type of illumination used in the embodiment.Such an optimization may produce various embodiments each suited forspecific cases. For example, an OID 100 for imaging the eyes of cats anddogs (i.e., veterinary use) may employ a different embodiment than theembodiment used for imaging human adults. Similarly, an OID 100 mayemploy a different embodiment for imaging infant (premature orotherwise), toddler, pre-pubescent, or adolescent eyes. The OID 100 mayemploy an Optical Assembly A 120 with adjustable elements that can betuned for the subject and application prior to imaging. In oneembodiment, an opaque eye covering unit can be used to prevent ambientlight from reaching the subject's eye 170 so as to cause natural pupildilation, improving the FOV illuminated and imaged.

FIG. 6 shows a schematic of the OID 100 and an embodiment of a mechanismused to induce a subject to fixate the gaze to facilitate imageacquisition of the appropriate region of the target tissue 175. Toreduce the variability in the focal length of the subject's eyes, thesubject can be instructed to fixate his/her gaze using the non-imagedeye 630, on an object that is far (for example, greater than 5 meters,an approximation for infinity) or at a virtual image of a dummy objectthat achieves the same effect. Such a virtual image 615 can be producedusing appropriate optics by a module in the OID 100. In this embodiment,an optical system 600 is positioned in front of the non-imaged eye 630for gaze fixation. The optical system 600 includes an optical assemblythat comprises one or more lenses and an object 615 localized at a depthclose to the focal plane of the optical assembly. In the focal plane,the object's coordinates may be predetermined or determined by the userat the time of imaging. Placing the object in the focal plane will causethe subject's eye to visualize the virtual image (O′) 615 of the objectformed far away (greater than 5 meters). If the object is placedprecisely in the focal plane, the image will be theoretically formed at‘infinity’. Due to natural tendency, the imaged eye 635 will also focusat the same depth, thus setting the focal length of the imaged eye 635within an expected range. Such a focal length of a set of eyes fixatedon an image that is far away would be approximately equal to thediameter of the eye, that is, approximately 20 mm for an average humanadult (smaller for younger humans and smaller animals). The in-planepositioning (x₀, y₀) of the object will determine the angle of theoptical axis of the eye with respect to the optical axis of the OID.Thus, by choosing (x₀, y₀), it becomes possible to image differentregions of the retina—that is, the imaged FOV may now include someperipheral regions that would not lie within the FOV otherwise. Theobject may thus be replaced by a screen or a two-dimensional photographand the subject be instructed to fixate on some predetermined featuresprior to each imaging event.

FIG. 7 illustrates an exemplary embodiment for immobilizing the OID 100with respect to the subject's eye 170. In some embodiments, the OID 100attaches temporarily or permanently to a rigid component (e.g., anose-bridge, rubber cup, sunglasses, or goggles) that immobilizes theOID 100 with respect to the imaging target. In some embodiments, therigid component is designed to block ambient light from reaching theeye, creating an artificial dark environment to cause natural pupildilation. A gaze fixation device 600 can be incorporated into theembodiment as a temporary or permanent attachment to the rigidcomponent. In this embodiment, the rigid component is a pair ofeyeglasses 700 used to minimize motion artifact by resting stably on thenose-bridge and the ears while imaging is performed. In anotherembodiment, optical fibers can guide light from the illumination module110 bidirectionally to and from the eyeglasses 700 and the OID 100. Inanother embodiment, waveguides etched into the plastic or glass of theeyeglasses can guide light from the illumination module 110bidirectionally to and from the subject's eye.

FIGS. 8A and 8B illustrate various embodiments for the incorporation ofan OID 810 into a standalone system 800 that can be operated bynon-experts using a simple user interface 820. FIG. 8A illustrates oneembodiment in which the user interface 820 is a touch screen thatautomates the image acquisition, storage, and transmission processes.Such a user interface 820 may also include a method for acceptingpayment (e.g., a credit card reader) to bill the customer for theimaging services. In this embodiment, the OID 810 is stationary, thuspermitting the subject to position his/her eye(s) in alignment with theimaging axis and rest the head/face against a rigid support to mitigatemotion artifact. In another embodiment, the OID 811 is connected throughelectrical cables and/or optical fibers to a rigid object that rests onthe subjects' head (e.g., a helmet, goggles, glasses). In thisembodiment, some elements of the OID 811 can be contained in the housingof the interface 820.

FIG. 8B illustrates an embodiment in which an OID 812 is used inconjunction with a mobile computing platform 855 (e.g., a smartphone ortablet computer). In this embodiment, the mobile computing platform 855contains one or more power modules, processor modules, image acquisitionmodules, communications modules, storage modules, and user interfacemodules 853. The communications module of the mobile computing platform855 can include either wireless or wired mechanisms or both. In thisembodiment, the OID 812 contains one or more illumination modules 805,one or more beam deflectors 817 to direct the one or more illuminationpaths 816 toward the one or more Optical Assembly A 820, one or moreOptical Assembly B 830, and one or more processor modules 850. The OID812 can contain a telemetry module 851 to communicate with the mobilecomputing platform 855 or to an external device. The OID 812 can containa power module 854 to power some or all of the electronic elements ofthe OID 812 or the mobile computing platform 855. The OID 812 canconnect to and communicate with the mobile computing platform 855through a wired mechanism 852. In another embodiment, some or all of theprocessing capabilities can be performed using the mobile computingplatform 855. In another embodiment, the mobile computing platform 855can be used to replace or provide alternate capabilities of some or allof the power modules, processor modules, image acquisition modules,communication modules, storage modules, and illumination modules.

FIG. 9 is a flowchart illustrating a method for using the OID 100 toacquire images of the target tissue 175 in accordance with theembodiments of the subject technology. The first step 910 is toimmobilize the OID 100 with respect to the subject's eye 170. Thisimmobilization step 910 can be achieved manually with either theoperator holding the OID 100 as steady as possible, positioning the faceagainst the OID 100 as steady as possible, or using one of variousembodiments (e.g., chin rest, eyeglasses, goggles, or a helmet) thatachieve a similar function. In one embodiment, this immobilization step910 is achieved through the use of a covering that rests gently on theface around the eye.

The second step 920 involves fixating the subject's gaze on a targetthat is either predetermined or determined dynamically by the operator.In both cases, fixation can be achieved through control of the gazefixation mechanism 600. In some cases, the subject may also be theoperator (e.g., in the case of a standalone system).

The third step 930 is to adjust one or more of Optical Assembly A 120and Optical Assembly B 130 such that an image is formed on the imagingsensor 145 with acceptable focus and clarity. In this third step 930,the illumination module 110 may also be adjusted (e.g., to achieve theappropriate type of illumination and the appropriate intensity ofillumination). In one embodiment, the illumination module 110 isadjusted to invoke white or green light illumination. The adjustment ofone or more of Optical Assembly A 120, Optical Assembly B 130, and theillumination module 110 may be done manually by the operator,semi-automatically, or automatically by the processor unit 150.

The fourth step 940 includes setting of one or more of the followingimage acquisition parameters: exposure time, gain (or pixelsensitivity), number of images, frequency of image frame acquisition (orframe rate), timing sequence, and pixel resolution and/or pixel area.Exposure time over which the imaging sensor 145 integrates light has adirect bearing on sensitivity and saturation of images during an imagingsession. Exposure time also determines the level of proportionalitybetween laser speckle contrast and velocity of light scatterers (e.g.,red blood cells) in the imaged specimen. Exposure times that are smallerthan 100 milliseconds are typical for LSCI. Exposure times forfluorescence imaging may be longer (up to 2 seconds). Gain (orsensitivity of pixel output to light intensity) of the imaging sensor145, in some embodiments, may be adjustable. In such embodiments, theadjustable gain mechanism allows, for the same number of photonsreaching the imaging sensor 145, the output of the imaging sensor 145 tobe higher or lower depending on the gain value. The number of imagesrefers to the total images acquired in an image stack for a given imageacquisition. The number of images can be one or more for a given ROI.Frequency of image frame acquisition (frame rate) is the number of imageframes to be acquired in 1 second and often depends on the imageacquisition device and its ability to communicate with a temporary orpermanent storage device. In some CMOS cameras, for example, it ispossible to achieve a frame rate that is the inverse of the cameraexposure time. Timing sequence refers to specific times or timeintervals for which the imaging sensor 145 acquires images and mayincorporate appropriate time delays between subsequent imageacquisitions. Pixel resolution and/or pixel area refers to the number ofpixels that are used to capture an image of the ROI. For example, theentire extent of a certain ROI 6.4 mm×5.12 mm in size may be acquired ata reduced 640 pixel×512 pixel resolution as opposed to a high 1280pixel×1024 pixel resolution by setting 2×2 high-resolution pixels as onemodified low-resolution pixel. In this case, the imaged area remains thesame. Also, only 640×512 contiguous high-resolution pixels may be usedto obtain one-fourth the extent of the ROI. In this case, the pixelresolution is still high but the imaged area (or pixel area) decreases.

The fifth step 950 is to acquire one or more images of the ROI under theillumination parameters established in the fourth step 940.

The sixth step 960 is to store the images acquired in the fifth step 950for subsequent processing. In some embodiments, these acquired imagescan be stored locally on the OID 100 (e.g., RAM, magnetic or solid statehard disk technology, flash disk technology, or optical disktechnology). In some embodiments, these acquired images can be storedremotely on an external storage device. In some embodiments, theseacquired images can be stored temporarily on the OID 100. Local storagecan be achieved using a memory element permanently or temporarilyembedded in the OID 100. Remote storage involves the use of a datatransmission channel.

The seventh step 970 is to determine whether additional images must beobtained under different settings (e.g., under a different illuminationmodality, adjustment parameter, or ROI). In one embodiment, afteracquiring a reflectance image of the retina, the illumination module 110is adjusted to green or red laser illumination for the OID to be able toperform LSCI. The third step 930 through the sixth step 960 are repeatedas necessary for the desired application.

The last step 980 is to process the images acquired in the fifth step950. In some embodiments, this last step 980 consists of one or more ofthe following:

Processing for LSCI. Speckle contrast may be calculated as the ratio ofstandard deviation and mean of pixel intensities in a neighborhood ofpixels. The neighborhood of pixels around a pixel P may be derived fromeither or both of spatial and temporal domains, that is the pixelscomprising the neighborhood may be spatially adjacent to the pixel P, orthe pixels comprising the neighborhood may lie at the same location as Pbut in adjacent (in time) image frames, or the pixels comprising theneighborhood may lie both spatially adjacent to pixel P in the sameframe and also in adjacent frames. The speckle contrast values may alsobe averaged either spatially or temporally. The neighborhood may bespatially isotropic, where the neighborhood may comprise the same numberof pixel in every direction about the pixel P, or anisotropic, where theneighborhood be preferentially oriented in one or more directions (e.g.,along the direction of blood flow in vessels, or along the axialdirection of blood vessels). Various ways of choosing neighborhoods andcalculating laser speckle contrast is described in (1). The specklecontrast may be used, for example, to:

-   -   Obtain high-resolution images of blood vessels in the eye with        high distinguishability from the background tissue, in healthy        situations as described for brain vasculature in (2), as well as        in abnormal situations as described for skin vasculature in (3);    -   Obtain images of blood flow in the eye, as described for brain        vasculature in (4); and    -   Obtain images of microvessel density in one or more regions of        the eye, as described for brain tumor vasculature in (5).

Feature extraction using a combination of one or more of LSCI,spectroscopic, and fluorescence images. This processing method mayinclude:

-   -   vessel segmentation using intensity-based thresholds, ridge        detection, or ridge tracking algorithms;    -   extracting vessel centerlines using morphological operations on        the segmented vessels;    -   diameter estimation using edge detection techniques, or ridge        detection techniques, as described for brain/meningeal        vasculature in (6);    -   distinguishing between arteries and veins using a combination of        spectroscopic images (in which arteries and veins have different        light absorption properties) and LSCI images (in which arteries        and veins have different blood velocities).

Any of the processing methodologies disclosed in prior art (7) and (8).

Registration of the acquired images to one another. The saidregistration may be done for multiple images of the same ROI, as isimplemented in (9) for mitigating the effect of motion artifact on LSCI;or for images of adjacent ROIs to build a mosaic or panoramic view of alarger ROI. Registration of acquired images to one another may beachieved prior to laser speckle contrast calculation, though anintermittent calculation of speckle contrast may facilitate theidentification of features useful for registration, as described in (9).

Spectroscopic imaging. This processing method includes combining imagesobtained under different illumination either pixel-wise or feature-wiseusing a combination of mathematical functions (e.g., addition,subtraction, scalar multiplication, and power functions). Images may benormalized based on mean or a certain percentile of intensity valueswithin the image or image stack, before the processing is done.

In some embodiments, this last step 980 consists of preparing the imagesacquired in the fifth step 950 for display on the OID 100 or an externaldisplay device (e.g., a smartphone, tablet, laptop, or other computingplatform). In some embodiments, this last step 980 consists oftransmitting the images acquired in the fifth step 950 for furtherprocessing on an external computing platform. In some embodiments, thislast step 980 consists of a combination of the processing methodsdescribed above. In some embodiments, the processed images are storedlocally on the OID 100 or on an external computing platform, or acombination thereof.

FIG. 10 is a flowchart illustrating the method for acquiring,processing, storing, and displaying the images obtained using the OID100. In this embodiment, the first step 1010 is to select an imagingmode, which includes one or more of the following:

-   -   Laser speckle contrast imaging.    -   Spectroscopic imaging.    -   Reflectance imaging.    -   Fluorescence imaging.

The second step 1020 is to trigger the acquisition of one or more imagesusing the one or more imaging modes selected in the first step 1010. Theacquisition of one or more images in the second step 1020 can betriggered manually, semi-automatically, or automatically.

The third step 1030 is to process the acquired images. In someembodiments, this third step 1030 consists of one or more of thefollowing:

Processing for LSCI. Speckle contrast may be calculated as the ratio ofstandard deviation and mean of pixel intensities in a neighborhood ofpixels. The neighborhood of pixels around a pixel P may be derived fromeither or both of spatial and temporal domains, that is the pixelscomprising the neighborhood may be spatially adjacent to the pixel P, orthe pixels comprising the neighborhood may lie at the same location as Pbut in adjacent (in time) image frames, or the pixels comprising theneighborhood may lie both spatially adjacent to pixel P in the sameframe and also in adjacent frames. The speckle contrast values may alsobe averaged either spatially or temporally. The neighborhood may bespatially isotropic, where the neighborhood may comprise the same numberof pixel in every direction about the pixel P, or anisotropic, where theneighborhood be preferentially oriented in one or more directions (e.g.,along the direction of blood flow in vessels, or along the axialdirection of blood vessels). Various ways of choosing neighborhoods andcalculating laser speckle contrast is described in (1). The specklecontrast may be used, for example, to:

Obtain high-resolution images of blood vessels in the eye with highdistinguishability from the background tissue, in healthy situations asdescribed for brain vasculature in (2), as well as in abnormalsituations as described for skin vasculature in (3);

-   -   Obtain images of blood flow in the eye, as described for brain        vasculature in (4); and    -   Obtain images of microvessel density in one or more regions of        the eye, as described for brain tumor vasculature in (5).

Feature extraction using a combination of one or more of LSCI,spectroscopic, and fluorescence images. This processing method mayinclude:

-   -   vessel segmentation using intensity-based thresholds, ridge        detection, or ridge tracking algorithms;    -   extracting vessel centerlines using morphological operations on        the segmented vessels;    -   diameter estimation using edge detection techniques, or ridge        detection techniques, as described for brain/meningeal        vasculature in (6);    -   distinguishing between arteries and veins using a combination of        spectroscopic images (in which arteries and veins have different        light absorption properties) and LSCI images (in which arteries        and veins have different blood velocities).

Any of the processing methodologies disclosed in prior are (7) and (8).

Registration of the acquired images to one another. The saidregistration may be done for multiple images of the same ROI, as isimplemented in (9) for mitigating the effect of motion artifact on LSCI;or for images of adjacent ROIs to build a mosaic or panoramic view of alarger ROI. Registration of acquired images to one another may beachieved prior to laser speckle contrast calculation, though anintermittent calculation of speckle contrast may facilitate theidentification of features useful for registration, as described in (9).

Spectroscopic imaging. This processing method includes combining imagesobtained under different illumination either pixel-wise or feature-wiseusing a combination of mathematical functions (e.g., addition,subtraction, scalar multiplication, and power functions). Images may benormalized based on mean or a certain percentile of intensity valueswithin the image or image stack, before the processing is done.

The fourth step 1040 is to determine whether storage of the acquiredimages is external from the OID 100. If remote storage of the acquiredimages is selected in the fourth step 1040, then the next step 1045 isto transmit one or more of the acquired and/or processed images to theremote storage device.

The fifth step 1050 is to store one or more of the acquired and/orprocessed images in the selected storage location. In some embodiments,the selected storage location is embedded permanently or temporarily inthe OID 100. In some embodiments, the selected storage location is oneor more external storage systems, including, for example, a smartphone,tablet, laptop, cloud computing system (e.g., a remote patientmonitoring system or a mobile disease management system), or othercomputing platform (e.g., desktop computer or web server). The OID 100can connect to the one or more selected storage locations via acombination of wired or wireless means.

The sixth step 1060 is to display the acquired and/or processed imagesfor review by the user. The display can consist of one or more of aliquid crystal display (LCD) screen or its equivalent embedded in theOID 100 or a similar screen embedded in an external system (e.g., asmartphone, tablet, laptop, or other computing platform). The sixth step1060 can include the use of display software to facilitate visualizationof the acquired and/or processed images or to allow the user tomanipulate the acquired and/or processed images.

The second step 1020 through the sixth step 1060 can be repeatedsequentially or simultaneously for each imaging mode selected in thefirst step 1010.

FIG. 11 is a flowchart illustrating a method for analyzing imagesobtained using the OID 100 and stored in an electronic patient recordsystem for disease progression assessment and management. In thisembodiment, the first step 1110 is to select a patient record toanalyze. The second step 1120 is to select one or more of images (I_(O)through I_(N)) stored in the patient's record for further analysis. Inone embodiment, the images selected for analysis were obtained using anOID in the LSCI mode. The third step 1130 is to select one or moreparameters (P_(X) through P_(Y)) extracted from, for example, acombination of one or more of LSCI, spectroscopic, reflectance, andfluorescence images. Examples of parameters P_(X) through P_(Y) areblood flow, blood vessel diameters, microvessel density, and bloodoxygenation. The fourth step 1140 is to select display preferences forpresentation of the output of the analysis. The fifth step 1150 is totrigger analysis of the one or more of the images and/or parametersselected in the second step 1120 and the third step 1130. The next step1160 uses information from the display preferences from the fourth step1140 to determine whether to display the images in an overlay format.The next step 1161 uses information from the display preferences fromthe fourth step 1140 to determine whether to display parameters in anoverlay format. If the display preferences selected in the fourth step1140, the next steps 1162 and 1163 are to render the parameter valuesand image stack along with an interface for navigating through theimages and an interface for selecting/de-selecting parameters to berendered. If the display preferences from the fourth step 1140 do notinclude the image overlay option, the next step 1170 is to render theparameter values along with an interface for selecting/de-selectingparameters to be rendered. If the display preferences from the fourthstep 1140 include the image overlay option but not the parameter displayoption, the next step 1163 is to render the images without renderingparameter values. The last step 1190 is to trigger therapy manually,semi-automatically, or automatically based on the one or more analyzedimages and/or parameters. In one embodiment, the last step 1190 consistsof a recommendation to the user to change a specific drug medication orto perform some other treatment procedure. In another embodiment, thelast step 1190 consists of a recommendation that allows the user totrigger an automatic treatment or procedure (e.g., an electronicprescription). In another embodiment, the last step 1190 consists of anautomated signal that controls a treatment mechanism (e.g., laserphotocoagulation).

FIGS. 12A and 12B are schematics for various embodiments of a diseasemonitoring/management system 1200 incorporating the OID 100. As shown inFIG. 12A, a disease monitoring/management system 1200 can incorporateone or more sensors, processors, storage units, interfaces, and datacommunication mechanisms and be used for the purpose of facilitating themonitoring of a patient by a remote caregiver or managing diagnosis ortreatment of one or more diseases (e.g., diabetes, hypertension, DR, HR,ROP, AMD, retinal detachment, glaucoma, cataract, choroidalneovascularization). In one embodiment, the diseasemonitoring/management system 1200 is designed for management of diabetesand includes an OID 100 and other diabetes sensors 1210 (e.g., bloodglucose meters, continuous glucose monitors, infusion pumps, weightscales, exercise sensors, food consumption sensors, electronic journals,EHRs, and laboratory information systems (LIS)). Data from these sensors100 and 1210 (e.g., blood glucose measurements, hemoglobin A1c values,calorie consumption, exercise activity, weight, height, age, sex,socio-economic status) and derivative data therefrom can be recorded ina storage unit 1220 (e.g., a RAM technology, magnetic, or solid statehard disk technology, flash disk technology, or optical disktechnology). All or any portion of the archived data can be retrievedfrom the storage unit 1220 as necessary for any combination ofprocessing by the analysis unit 1230, presentation to the user by thedisplay/access unit 1250, and transfer to an external device (e.g., forstorage, display, or processing) by the communication unit 1240.

The storage unit 1220 can be embedded in one or more storage units,including an EHR system, a picture archiving and communications system(PACS), an OID 100, or any of the sensors in the diseasemonitoring/management system 1200.

The analysis unit 1230 can be embedded in one or more hardware orsoftware devices, including an EHR system, a picture archiving andcommunications system (PACS), an OID 100, or any of the sensors in thedisease monitoring/management system 1200. The analysis unit 1230 canprocess any or all of the data or derivative data. In one embodiment,the analysis of data for determining a triggering event (e.g., the riskof diabetic retinopathy) includes any combination of the following:blood flow in the retina, blood vessel density in one or more ROIs ofthe retina, blood vessel diameter in the retina, blood vessel diameterratios in one or more ROIs of the retina, classification of vessels asarteries or veins, blood glucose measurements, blood pressure, exerciseactivity, calorie consumption, retinal images, and laboratory testresults.

The communication unit 1240 can consist of any telecommunications deviceor computing platform capable of transmitting data wirelessly or via awired connection to another computing platform, including a smartphone,pager, laptop or personal computer, fax machine. In some embodiments,the communication unit 1240 is used to transmit data along withderivative data (e.g., information that has been derived frommathematically processing the data), including indices of aggregateddata, image overlays, reports generated from some or all of the data,and alarms or other notifications generated based on analysis of thedata or derivative data. In some embodiments, the diseasemonitoring/management system 1200 uses the communication unit 1240 totransmit a message to a patient, caregiver, healthcare provider, orfamily member. The message can take the form of one or more electronicmail, instant message, short message service (i.e., text messaging),phone call, fax, paging service (i.e., pager), direct mail (i.e., postalservice), and personal communication. The message can be tailored to therecipient. For example, if the recipient is a physician or healthcareprovider, the message could be to call the patient into the office foran appointment or to call another provider for more information. If themessage is for the patient, the message could be to call the provider toset up an appointment or to inform the patient of disease risk (e.g.,onset of diabetic retinopathy) or the need to improve certain aspects oftheir disease management (e.g., improving exercise, diet, or medicationcompliance). The messages could also be educational in nature (e.g.,general information about the disease). The messages could automaticallytrigger an event in another device (e.g., an EHR or computerized orderentry system). This event could be, for example, to set up anappointment for the patient in the hospital scheduling system or torecommend a specific change to the disease management regimen. Themessage can originate from any device within the diseasemonitoring/management system 1200, including an OID 100, an EHR, orblood glucose meter.

The display/access unit 1250 can consist of one or more of a combinationof hardware and software systems designed to allow a user to accessand/or visualize the data or derivative data, including an OID 100, aweb-based application/portal, a mobile software application, astandalone software application, a software application embedded in anEHR system, or a software application embedded in another device.

FIG. 12B is a schematic of one embodiment that contains an OID 100, acentral communication/storage system (e.g., an EHR system or PACS) 1241,a plurality of patient sensors 1210, and a plurality of useraccess/display devices 1250. In this embodiment, the OID 100 containsone or more image acquisition units 1201 containing one or more imagingsensors for capturing and converting light along the imaging path 135 toan electronic format, one or more storage units 1202 for temporarily orpermanently storing said reflected illumination in an electronic format,one or more image analysis units 1203 for processing and analyzing saidreflected illumination stored in an electronic format, and one or morecommunication/data transmission units 1242 for bidirectionalcommunication with the central communication/storage system 1241. Inthis embodiment, the plurality of patient sensors 1210 consists of oneor more blood glucose meters 1211 for measuring daily blood glucosevalues, one or more behavioral sensors for monitoring exercise activityand calorie consumption, and one or more communication/data transmissionunits 1244 for bidirectional communication with the centralcommunication/storage system 1241. In this embodiment, the plurality ofuser access/display devices 1250 consists of one or more web portals ordashboards 1251 accessible through a plurality of computing platforms(e.g., smartphone, table, or laptop), one or more mobile applications1252 accessible through a plurality of mobile computing platforms (e.g.,smartphone or tablet), and one or more communication/data transmissionunits 1243 for bidirectional communication with the centralcommunication/storage system 1241. In this embodiment, the one or moreweb portals or dashboards 1251 and one or more mobile applications 1252allow the user to view multiple patient records and patient-specificdata stored on or accessible through the central communication/storagesystem 1241.

FIGS. 13A, 13B, and 13C illustrate various embodiments for presentingand assessing parameters generated using the OID 100 in accordance withthe various embodiments of the subject technology. FIG. 13A presents agraph of data generated using the OID 100. The data can be presented asindividual data points 1314, a trending plot 1315, a change in datapoint values 1317 and 1318, or a combination thereof. The data can bepresented as a function of time 1311, where each data point 1314 isplotted sequentially from the first point to 1312 to the last pointt_(N) 1313 in a chronological, reverse chronological, or other orderingsystem. In one embodiment, the data points 1314 are blood vesseldiameter values for a specific blood vessel in the ROI of the retinaobtained using an OID 100 with LSCI functionality. In one embodiment,the data points 1314 are blood flow values for a specific blood vesselin the ROI of the retina obtained using an OID 100 with LSCIfunctionality. In one embodiment, the data points 1314 are blood vessellength values for a specific blood vessel in the ROI of the retinaobtained using an OID 100 with reflectance imaging functionality. In oneembodiment, the data points 1314 or trend plot 1315 are presented withdata points or trend plots of more than one blood vessel or ROI. Analgorithm embedded in the OID 100 or the disease monitoring/managementsystem 1200 can analyze a single data point 1314 or the trend 1315 todetermine the functional properties of the blood vessel or the retina,or the risk of a disease or condition (e.g., diabetic retinopathy). Inone embodiment, interpolation is used to estimate missing data pointsand extrapolation based on trends is used to estimate data points notyet obtained. In the same or another embodiment, curve fittingapproaches are used to find and address (to prevent discarding)seemingly aberrant data points. In another embodiment, the algorithmuses a threshold 1316 to determine whether the value of a data point1314 suggests, for example, an increased risk for a disease or condition(e.g., diabetic retinopathy). In another embodiment, the algorithm usesthe change in data point values between two consecutive points todetermine whether a threshold has been crossed. For example, the slopeof lines 1317 and 1318 can be compared to the slope of line 1319, whichacts as the slope threshold for determining the significance of thechange in the data points. The slope of lines 1317 and 1318 can becompared to each other to determine the significance of the change.Thresholds 1316 and 1319 can be pre-determined based on the individualpatient, a patient population dataset, or some other benchmark.Thresholds 1316 and 1319 can be adjusted automatically or manually. FIG.13B represents the use of multiple thresholds to, for example,characterize the degree of conformance of the data to a set standard. Inthis embodiment, certain data points fall within a region of highconformance 1326, while others fall within a region of moderateconformance 1327, and yet others fall within a region of low conformance1328. As with thresholds 1316 and 1319, these regions of conformance1326, 1327, and 1328 can be pre-determined based on the individualpatient, a patient population dataset, or some other benchmark and canbe adjusted automatically or manually. FIG. 13C represents the use ofmultiple thresholds to, for example, stratify risk levels. In thisembodiment, certain data points fall within the lowest risk level 1336,while others fall within a moderate risk level 1337, and yet others fallwithin a high risk level 1338. As with thresholds 1316 and 1319, theserisk levels 1336, 1337, and 1338 can be pre-determined based on theindividual patient, a patient population dataset, or some otherbenchmark and can be adjusted automatically or manually.

The foregoing description is provided to enable a person skilled in theart to practice the various configurations described herein. While thesubject technology has been particularly described with reference to thevarious figures and configurations, it should be understood that theseare for illustration purposes only and should not be taken as limitingthe scope of the subject technology.

There may be many other ways to implement the subject technology.Various functions and elements described herein may be partitioneddifferently from those shown without departing from the scope of thesubject technology. Various modifications to these configurations willbe readily apparent to those skilled in the art, and generic principlesdefined herein may be applied to other configurations. Thus, manychanges and modifications may be made to the subject technology, by onehaving ordinary skill in the art, without departing from the scope ofthe subject technology.

It is understood that the specific order or hierarchy of steps in theprocesses disclosed is an illustration of exemplary approaches. Basedupon design preferences, it is understood that the specific order orhierarchy of steps in the processes may be rearranged. Some of the stepsmay be performed simultaneously. The accompanying method claims presentelements of the various steps in a sample order, and are not meant to belimited to the specific order or hierarchy presented.

A phrase such as “an aspect” does not imply that such aspect isessential to the subject technology or that such aspect applies to allconfigurations of the subject technology. A disclosure relating to anaspect may apply to all configurations, or one or more configurations.An aspect may provide one or more examples of the disclosure. A phrasesuch as “an aspect” may refer to one or more aspects and vice versa. Aphrase such as “an embodiment” does not imply that such embodiment isessential to the subject technology or that such embodiment applies toall configurations of the subject technology. A disclosure relating toan embodiment may apply to all embodiments, or one or more embodiments.An embodiment may provide one or more examples of the disclosure. Aphrase such “an embodiment” may refer to one or more embodiments andvice versa. A phrase such as “a configuration” does not imply that suchconfiguration is essential to the subject technology or that suchconfiguration applies to all configurations of the subject technology. Adisclosure relating to a configuration may apply to all configurations,or one or more configurations. A configuration may provide one or moreexamples of the disclosure. A phrase such as “a configuration” may referto one or more configurations and vice versa.

As used herein, the phrase “at least one of” preceding a series ofitems, with the terms “and” or “or” to separate any of the items,modifies the list as a whole, rather than each member of the list (i.e.,each item). The phrase “at least one of” does not require selection ofat least one item; rather, the phrase allows a meaning that includes atleast one of any one of the items, and/or at least one of anycombination of the items, and/or at least one of each of the items. Byway of example, the phrases “at least one of A, B, and C” or “at leastone of A, B, or C” each refer to only A, only B, or only C; anycombination of A, B, and C; and/or at least one of each of A, B, and C.

Terms such as “top,” “bottom,” “front,” “back” and the like as used inthis disclosure should be understood as referring to an arbitrary frameof reference, rather than to the ordinary gravitational frame ofreference. Thus, a top surface, a bottom surface, a front surface, and aback surface may extend upwardly, downwardly, diagonally, orhorizontally in a gravitational frame of reference.

Furthermore, to the extent that the term “include,” “have,” or the likeis used in the description or the claims, such term is intended to beinclusive in a manner similar to the term “comprise” as “comprise” isinterpreted when employed as a transitional word in a claim.

The word “exemplary” is used herein to mean “serving as an example,instance, or illustration.” Any embodiment described herein as“exemplary” is not necessarily to be construed as preferred oradvantageous over other embodiments.

As used herein, the term “real time” shall be understood to mean theinstantaneous moment of an event or condition, or the instantaneousmoment of an event or condition plus short period of elapsed time usedto make relevant measurements, optional computations, etc., andcommunicate the measurement, computation, or etc., wherein the state ofan event or condition being measured is substantially the same as thatof the instantaneous moment irrespective of the elapsed time interval.Used in this context “substantially the same” shall be understood tomean that the data for the event or condition remains useful for thepurpose for which it is being gathered after the elapsed time period.

A reference to an element in the singular is not intended to mean “oneand only one” unless specifically stated, but rather “one or more.”Pronouns in the masculine (e.g., his) include the feminine and neutergender (e.g., her and its) and vice versa. The term “some” refers to oneor more. Underlined and/or italicized headings and subheadings are usedfor convenience only, do not limit the subject technology, and are notreferred to in connection with the interpretation of the description ofthe subject technology. All structural and functional equivalents to theelements of the various configurations described throughout thisdisclosure that are known or later come to be known to those of ordinaryskill in the art are expressly incorporated herein by reference andintended to be encompassed by the subject technology. Moreover, nothingdisclosed herein is intended to be dedicated to the public regardless ofwhether such disclosure is explicitly recited in the above description.

While certain aspects and embodiments of the invention have beendescribed, these have been presented by way of example only, and are notintended to limit the scope of the invention. Indeed, the novel methodsand systems described herein may be embodied in a variety of other formswithout departing from the spirit thereof. The accompanying claims andtheir equivalents are intended to cover such forms or modifications aswould fall within the scope and spirit of the invention.

What is claimed is:
 1. An ophthalmic imaging device, comprising: A) anillumination module capable of generating a plurality of illuminationmodalities, wherein the illumination modalities include coherentillumination and incoherent illumination, and wherein the illuminationmodule is configured to perform one or more of laser speckle contrastimaging, spectroscopic imaging, reflectance imaging, or fluorescenceimaging; B) one or more imaging sensors configured to collect light fromone or more regions of tissue of the eye; C) (i) an optical assemblycomprising one or more optical elements configured to direct light fromthe illumination module to the one or more regions of tissue of the eye,and further configured to direct light from the one or more regions oftissue of the eye to the one or more imaging sensors; or (ii) a firstoptical assembly comprising one or more first optical elementsconfigured to direct light from the illumination module to the one ormore regions of tissue of the eye and a second optical assemblycomprising one or more second optical elements configured to directlight from the one or more regions of tissue of the eye to the one ormore imaging sensors; and D) one or more processors configured tocalculate laser speckle contrast values for pixels of the one or moreimaging sensors associated with the one or more regions of tissue of theeye, wherein the calculated laser speckle contrast values use propertiesof a pixel's neighborhood of pixels in spatial or temporal domains;wherein the one or more regions of the tissue of the eye include theretina, choroid, the cornea, the sclera, and the eye lens; wherein theone or more optical elements, the one or more first optical elements,and/or the one or more second optical elements is an aperture thatresults in the production of a speckle pattern on the one or moreimaging sensors.
 2. The ophthalmic imaging device of claim 1, whereinthe one or more processors are further configured to control thearrangement of the one or more optical elements, to control durations,duty cycles, and synchrony of the plurality of illumination modalities,and the one or more imaging sensors, to control one or more imageacquisition parameter, or to process data generated from the one or moreimaging sensors to perform one or more of laser speckle contrastimaging, spectroscopic imaging, reflectance imaging, and fluorescenceimaging.
 3. The ophthalmic imaging device of claim 1, further comprisingone or more means of user input.
 4. The ophthalmic imaging device ofclaim 1, further comprising one or more means of data transmission touni-directionally or bi-directionally exchange information with one ormore storage devices, display devices, or processors that may be local,standalone, or associated with one or more remote computers or servers.5. The ophthalmic imaging device of claim 1, (i) wherein the one or moreoptical elements are configured to control an intensity, wavelengthrange, beam shape, beam size, and/or beam position of the light from theillumination module or (ii) wherein the one or more first opticalelements are configured to control the intensity, wavelength range, beamshape, beam size, and/or beam position of the light from theillumination module.
 6. The ophthalmic imaging device of claim 1,wherein the one or more processors are further configured to extractinformation from the calculated laser speckle contrast values, whereinthe extracted information includes estimates of blood velocity,estimates of blood flow, blood vessel diameters, spatial density ofblood vessels, or classification of blood vessels as arterioles orvenules.
 7. The ophthalmic imaging device of claim 1, wherein the one ormore processors are further configured to acquire an image stack and toregister images of the acquired image stack to a reference image,wherein the reference image is acquired independently or is one of theimages in the acquired image stack.
 8. The ophthalmic imaging device ofclaim 1, further comprising an immobilization mechanism forstabilization with respect to the subject's eye, wherein theimmobilization mechanism comprises one or more immobilization opticalelements and one or more rigid components, wherein the one or moreimmobilization optical elements includes lenses, filters, mirrors,collimators, beam splitters, fiber optics, light sensors, and aperturesand the one or more rigid components includes a helmet or one or morenose bridges, sunglasses, goggles, rubber cups, or helmets.
 9. Theophthalmic imaging device of claim 1, wherein the light directed to theone or more regions of tissue of the eye from the illumination moduleoccurs synchronously or asynchronously.
 10. The ophthalmic imagingdevice of claim 1, further comprising one or more kinematic elements forengaging, indexing, or linear translation of the one or more opticalelements, wherein the one or more kinematic elements includes steppermotors, rotors, gears, and guide rails.
 11. The ophthalmic imagingdevice of claim 1, further comprising a gaze fixation mechanism tofacilitate fixation of the eye's gaze on a specified physical or virtualtarget using the contralateral, non-imaged eye;
 12. The ophthalmicimaging device of claim 11, wherein the gaze fixation mechanismcomprises an optical assembly comprising one or more fixation opticalelements including lenses, filters, mirrors, collimators, beamsplitters, fiber optics, light sensors, and apertures.
 13. Theophthalmic imaging device of claim 11, wherein the gaze fixationmechanism comprises one or more kinematic elements to adjust one or morefixation optical elements.
 14. The ophthalmic imaging device of claim11, wherein the gaze fixation mechanism projects an image of a physicalor virtual object at a specified target location with respect to theimaged eye or the contralateral eye, wherein the projected image isdetermined prior to or at the time of imaging and the projected imagelocation varies during the course of imaging to facilitate acquisitionof images of different regions of the eye.
 15. The ophthalmic imagingdevice of claim 11, wherein the gaze fixation mechanism furthercomprises a display unit that generates one or more virtual objects, theprojected images of which coincide with the intended target for gazefixation.
 16. The ophthalmic imaging device of claim 11, wherein thegaze fixation mechanism further comprises a processing element tocontrol operation of the gaze fixation mechanism and to perform one ormore calculations for the operation of the gaze fixation mechanism,wherein the one or more calculations include calculations pertaining tolocation identification of the intended target of gaze fixation andlocation identification of the virtual or physical object.